Five unrelated children have been described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, autoimmune phenomena and expanded populations of TCR/CD3+, CD4-, CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child was found to have defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when co-expressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this newly recognized disorder of lymphocyte homeostasis and peripheral self-tolerance. Further studies of family members revealed one extended family in which a dominant negative Fas mutation segregated with clinical abnormalities ranging from benign lymphadenopathy to autoimmune disease with elevated double negative T cells to Hodgkin's disease, diagnosed in 2 individuals after several years of benign adenopathy. The possibility that Fas and other proteins which participate in lymphocyte apoptosis might function as oncogenes in the development of Hodgkin's disease is being pursued.